3-(3,5-Disubstituted-4-hydroxyphenyl)propionamide derivatives as cathepsin b inhibitors

ABSTRACT

The present invention is directed to novel 3-(3,5-disubstituted-4-hydroxyphenyl)-propionamide derivatives that are inhibitors of Cathepsin B. Pharmaceutical composition comprising these compounds, method of treating diseases mediated by Cathepsin B, utilizing these compounds and methods of preparing these compounds are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention is directed to novel3-(3,5-disubstituted-4-hydroxyphenyl)-propionamide derivatives that areinhibitors of Cathepsin B. Pharmaceutical composition comprising thesecompounds, method of treating diseases mediated by Cathepsin B utilizingthese compounds and methods of preparing these compounds are alsodisclosed.

2. State of the Art

Cysteine proteases such as Cathepsins B, H, K, L, O and S, represent aclass of peptidases characterized by the presence of a cysteine residuein the catalytic site of the enzyme. Cysteine proteases are associatedwith the normal degradation and processing of proteins. The aberrantactivity of cysteine proteases, e.g., as a result of increase expressionor enhanced activation, however, may have pathological consequences. Inthis regard, certain cysteine proteases are associated with a number ofdisease states, including arthritis, muscular dystrophy, inflammation,tumor invasion, glomerulonephritis, malaria, periodontal disease,metachromatic leukodystrophy and others. For example, increasedCathepsin B levels and redistribution of the enzyme are found in tumorsthus suggesting a role for the enzyme in tumor invasion and metastasis.In addition, aberrant Cathepsin B activity is implicated in such diseasestates as rheumatoid arthritis, osteoarthritis, pneumocystis carinii,acute pancreatitis, inflammatory airway disease and bone and jointdisorders.

The prominent expression of Cathepsin K in osteoclasts andosteoclast-related multinucleated cells and its high collagenolyticactivity suggest that the enzyme is involved in ososteoclast-mediatedbone resorption and, hence, in bone abnormalities such as occurs inosteoporosis. In addition, Cathepsin K expression in the lung and itselastinolytic activity suggest that the enzyme plays a role in pulmonarydisorders as well.

Cathepsin L is implicated in normal lysosomal proteolysis as well asseveral disease states, including, but not limited to, metastasis ofmelanomas. Cathepsin S is implicated in Alzheimer's disease and certainautoimmune disorders, including, but not limited to juvenile onsetdiabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritisand Hashimoto's thyroiditis. In addition, Cathepsin S is implicated in:allergic disorders, including, but not limited to asthma; and allogeneicimmune reponses, including, but not limited to, rejection of organtransplants or tissue grafts.

Another cysteine protease, Cathepsin F, has been found in macrophagesand is involved in antigen processing. It is believed that Cathepsin Fin stimulated lung macrophages and possibly other antigen presentingcells could play a role in airway inflammation (see G. P. Shi et al, J.Exp. Med. 191, 1177, 2000).

In view of the number of diseases wherein it is recognized that anincrease in cysteine protease activity contributes to the pathologyand/or symptomatology of the disease, molecules which inhibit theactivity of this class of enzymes, in particular molecules whichselectively inhibit Cathepsins B, H, K, L, O and S, are desirable astherapeutic agents. The present invention fulfills this and relatedneeds.

SUMMARY OF THE INVENTION

The present invention provides3-(3,5-disubstituted-4-hydroxyphenyl)propionamide derivatives thatselectively inhibit Cathepsin B. Pharmaceutical compositions comprisingthese compounds are useful in the treatment of diseases mediated byCathepsin B.

Accordingly, in one aspect, the present invention is directed to acompound of Formula I:

wherein:

-   -   R¹ and R² are independently hydrogen, alkyl, haloalkyl,        hydroxyalkyl, aryl, or aralkyl; or    -   R¹ and R² together with the carbon atom to which they are        attached form cycloalkyl or heterocycloalkyl;    -   R³ is alkyl or iodo; and    -   R⁴ is selected from the group consisting of aryl, heteroaryl, or        heterocycloalkyl wherein R⁴ is optionally substituted with one,        two or three R^(a) wherein:        -   each R^(a) is independently selected from the group            consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, halo,            haloalkyl, haloalkoxy, nitro, amino, alkylamino,            dialkylamino, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,            dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl,            arylamino, heteroarylamino, heterocycloalkylamino, aryloxy,            heteroaryloxy, heterocycloalkyloxy, arylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone,            heteroarylthio wherein the sulfur may be oxidized to            sulfoxide or sulfone, heterocycloalkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,            carboxy, or alkoxycarbonyl wherein R^(a) is optionally            substituted with one, two or three R^(b) wherein:        -   each R^(b) is independently selected from the group            consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, halo,            haloalkyl, haloalkoxy, nitro, amino, alkylamino,            dialkylamino, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,            dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl,            arylamino, heteroarylamino, heterocycloalkylamino, aryloxy,            heteroaryloxy, heterocycloalkyloxy, arylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone,            heteroarylthio wherein the sulfur may be oxidized to            sulfoxide or sulfone, heterocycloalkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,            carboxy, or alkoxycarbonyl wherein each R^(b) is optionally            substituted with one, two or three substituents            independently selected from alkyl, alkoxy, hydroxy,            alkylthio wherein the sulfur may be oxidized to sulfoxide or            sulfone, halo, haloalkyl, haloalkoxy, carboxy,            alkoxycarbonyl, amino, alkylamino, dialkylamino,            aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,            aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,            cyano, or nitro;    -   R⁵ and R⁶ are independently hydrogen or alkyl;        or a pharmaceutically acceptable salt thereof.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a compound of Formula I, individual isomer,mixture of isomers or pharmaceutically acceptable salt thereof inadmixture with one or more pharmaceutically suitable excipients.

In a third aspect, this invention is directed to a method of treating adisease in an animal in which inhibition of Cathepsin B, can prevent,inhibit or ameliorate the pathology and/or symptomatology of thedisease, which method comprises administering to the animal apharmaceutical composition comprising a therapeutically effective amountof compound of Formula I, an individual isomer, mixture of isomers or apharmaceutically acceptable salt thereof. Preferably, the disease iscancer, rheumatoid arthritis, osteoarthritis, pneumocystis carinii,acute pancreatitis, inflammatory airway disease, bone and jointdisorders, stroke, alcoholic hepatitis, cholestatic liver diseases,hepatitis C, and fatty liver diseases.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this application and have themeanings given this section:

“Alkyl” means a straight or branched, saturated aliphatic radical havingthe number of carbon atoms indicated e.g., (C₁₋₆)alkyl includes methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, hexyl, and the like. Preferably, methyl, ethyl, propyl, orisopropyl.

“Alkylene” means a straight or branched, saturated aliphatic divalentradical having one to six carbon atoms unless otherwise indicated e.g.,methylene, ethylene, propylene, isopropylene, butylene, sec-butylene,isobutylene, tert-butylene, pentylene, hexylene, and the like.Preferably, methylene, ethylene, propylene, or isopropylene (includingall its isomers).

“Aryl” means an aromatic monocyclic or bicyclic ring containing 6-12carbon atoms unless otherwise indicated wherein each ring containedtherein is comprised of 6 annular members e.g., (C₆₋₁₄)aryl includesphenyl, naphthalenyl, or anthracenyl, preferably phenyl.

“Aralkyl” means a radical -alkylene)-R where R is an aryl group asdefined above, e.g., benzyl, phenylethyl, phenylpropyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g.,birds, etc.).

“Alkylthio” means a radical —SR where R is alkyl as defined above, e.g.,methylthio, ethylthio, propylthio (including all isomeric forms),butylthio (including all isomeric forms), and the like.

“Arylthio” means a radical —SR where R is aryl as defined above, e.g.,phenylthio, napthylthio, and the like.

“Amino” means a radical —NH₂, or an N-oxide derivative, or a protectedderivative thereof such as —NH→O, —NHBoc, —NHCBz, and the like.

“Arylamino” means a radical —NRR′ where R is hydrogen or alkyl and R′ isaryl as defined above, e.g., phenylamino, napthylamino, and the like.

“Acyl” means a radical —COR where R is alkyl, trifluoromethyl, aryl,heteroaryl, or heterocycloalkyl, e.g., methylcarbonyl,trifluoromethylcarbonyl, benzoyl, and the like.

“Alkylamino” means a radical —NHR where R is alkyl as defined above,e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-,tert-butylamino, methylamino-N-oxide, and the like.

“Alkoxy” means a radical —OR where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Aryloxy” means a radical —OR where R is aryl as defined above, e.g.,phenoxy, napthyloxy, and the like.

“Alkoxycarbonyl” means a radical —COOR where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, or2-propoxycarbonyl, n-, iso-, or tert-butoxycarbonyl, and the like.

“Aminocarbonyl” means a radical —CONH₂.

“Alkylaminocarbonyl” means a radical —CONHR where R is an alkyl group asdefined above e.g, methylaminocarbonyl, ethylaminocarbonyl, and thelike.

“Aminosulfonyl” means a radical —SO₂NH₂.

“Alkylaminosulfonyl” means a radical —SO₂NHR where R is an alkyl groupas defined above e.g, methylaminosulfonyl, ethylaminosulfonyl, and thelike.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to six carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl.

“Dialkylamino” means a radical —NRR′ where R and R′ are independentlyalkyl as defined above, or an N-oxide derivative, or a protectedderivative thereof, e.g., dimethylamino, diethylamino,methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, andthe like.

“Dialkylaminocarbonyl” means a radical —CONRR′ where R and R′ areindependently an alkyl group as defined above e.g,dimethylaminocarbonyl, methylethylaminocarbonyl, and the like.

“Dialkylaminosulfonyl” means a radical —SO₂NRR′ where R and R′ areindependently an alkyl group as defined above e.g,dimethylaminosulfonyl, methylethylaminosulfonyl, and the like.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition, which may be causedby, or incident to, medical or veterinary therapy applied to thatanimal, i.e., the “side effects” of such therapy.

“Halo” means fluoro, chloro, bromo or iodo.

“Haloalkyl” means an alkyl group as defined herein wherein one, two, orthree hydrogen atoms in the alkyl group has been replaced by a halogroup as defined above, e.g., trifluoromethyl, difluorochloromethyl,tribromomethyl, chlorofluoroethyl, dichlorofluoroethyl,chlorodifluoromethyl including all the isomeric forms thereof, and thelike.

“Haloalkoxy” means a radical —OR where R is haloalkyl as defined above,e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

“Heteroaryl” means an aromatic monocyclic or bicyclic ring containing 5to 9 ring atoms (unless otherwise indicated) wherein one, two, or threering atoms are heteroatoms independently selected from N, O, or S(O)n(wherein n is 0, 1, or 2), the remaining ring atoms being carbon.Representative examples include, but are not limited to, thienyl,furanyl, pyrrolyl, imidazolyl, pyrimidinyl, pyradizinyl, pyrazinyl,isoxazolyl, oxazolyl, indolyl, benzo[b]thienyl, isobenzofuranyl,purinyl, quinolinyl, isoquinolyl, pterdinyl, perimidinyl, pyridyl,pyrazolyl, [2,4′]bipyridinylyl, 2-phenylpyridinyl, and the like, ortetrazolyl. The definition of heteroaryl also includes the N-oxidederivatives (≡N⁺→O⁻) i.e., where the nitrogen atom in the ring isoxidized.

“Heteroaralkyl” means a radical -(alkylene)-R where R is heteroaryl asdefined above, e.g., pyridylmethyl, pyridylethyl, furanylmethyl,benzofuranylmethyl, and the like.

“Heteroarylamino” means a radical —NRR′ where R is hydrogen or alkyl andR′ is heteroaryl as defined above, e.g., pyridylamino, thienylamino,indolylamino, and the like.

“Heteroaryloxy” means a radical —OR where R is heteroaryl as definedabove, e.g., pyridyloxy, thienyloxy, furanyloxy, and the like.

“Heteroarylthio” means a radical —SR where R is heteroaryl as definedabove, e.g., pyridylthio, isoquinolinylthio, imidazolylthio and thelike.

“Heterocycloalkyl” means a saturated or partially unsaturated mono orbicyclic ring containing three to ten ring atoms wherein one, two, orthree of ring atoms are heteroatoms independently selected from N, O orS(O)_(n) (wherein n is 0, 1, or 2), the remaining ring atoms beingcarbon e.g., the term heterocycloalkyl includes tetrahydrofuranyl,piperidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl,morpholinyl, thiomorpholinyl, and the like. The definition ofheterocycloalkyl also includes the N-oxide derivatives (≡N⁺→O⁻) i.e.,where the nitrogen atom in the ring is oxidized.

“Heterocycloalkylalkyl” means a radical -(alkylene)-R where R isheterocycloalkyl as defined above, e.g., piperidinylmethyl,piperazinylethyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, and thelike.

“Heterocycloalkylamino” means a radical —NRR′ where R is hydrogen oralkyl and R′ is heterocycloalkyl as defined above, e.g.,tetrahydrofuranylamino, pyrrolidinylamino, and the like.

“Heterocycloalkyloxy” means a radical —OR where R is heterocycloalkyl asdefined above, e.g., piperidinyloxy, piperazinyloxy, pyrrolidinyloxy,tetrahydrofuranyloxy, and the like.

“Heterocycloalkylthio” means a radical —SR where R is heterocycloalkylas defined above, e.g., morpholinylthio, piperidinylthio, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Isomers” mean compounds of Formula I having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “steroisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center has two enantiomeric forms ofopposite chirality is termed a “racemic mixture”. A compound that hasmore than one chiral center has 2^(n-1) enantiomeric pairs, where it isthe number of chiral centers. Compounds with more than one chiral centermay exist as ether an individual diasteromer or as a mixture ofdiastereomers, termed a “diastereomeric mixture”. When one chiral centeris present a stereoisomer may be characterized by the absoluteconfiguration of that chiral center. Absolute configuration refers tothe arrangement in space of the substituents attached to the chiralcenter. Enantiomers are characterized by the absolute configuration oftheir chiral centers and described by the R- and S-sequencing rules ofCahn, Ingold and Prelog. Conventions for stereochemical nomenclature,methods for the determination of stereochemistry and the separation ofstereoisomers are well known in the art (e.g., see “Advanced OrganicChemistry”, 3rd edition, March, Jerry, John Wiley & Sons, New York,1985). It is understood that the names and illustration used in thisApplication to describe compounds of Formula I are meant to beencompassed all possible stereoisomers and any mixture, racemic orotherwise, thereof.

“Nitro” means the radical NO₂.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, the phrase “Ar is optionally substituted with—(C₁₋₆)alkyl” means that —(C₁₋₆)alkyl may but need not be present, andthe description includes situations where the Ar group is substitutedwith —(C₁₋₆)alkyl and situations where the Ar group is not substitutedwith —(C₁₋₆)alkyl.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is userul in preparing apharmaceutical composition that is generall safe, non-toxic and neitherbiologically nor otherwise undesirabale and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of FormulaI which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

The present invention also includes the prodrugs of a compound ofFormula I. Prodrugs means any compound which releases an active parentdrug according to Formula I in vivo when such prodrug is administered toa mammalian subject. Prodrugs of a compound of Formula I are prepared bymodifying functional groups present in the compound of Formula I in sucha way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of Formula I wherein ahydroxy, amino, or sulfhydryl group in compound I is bonded to any groupthat may be cleaved in vivo to regenerate the free hydroxyl, amino, orsulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of Formula I, and the like.

The present invention also includes the protected derivatives of acompound of Formula I. Protected derivatives means derivatives ofcompounds of Formula I in which a reactive site or sites are blockedwith protective groups. Protected derivatives of compounds of Formula Iare useful in the preparation of compounds of Formula I or in themselvesmay be active cysteine protease inhibitors. A comprehensive list ofsuitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981, thedisclosure of which is incorporated herein by reference in its entirety.

The present invention also includes the N-oxide derivative of a compoundof Formula I. N-oxide derivative of a compound of Formula I can formwhen a compound of Formula I carries a nitrogen atom at a position thatis susceptible to oxidation.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Treatment” or “teating” means any administration of a compound of thepresent invention and includes:

-   (1) preventing the disease from occurring in an animal, which may be    predisposed to the disease but does not yet experience or display    the pathology or symptomatology of the disease,-   (2) inhibiting the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    arresting further development of the pathology and/or    symptomatology), or-   (3) ameliorating the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    reversing the pathology and/or symptomatology).

Representative compounds of Formula I where R⁵ is hydrogen and othergroups are as defined below are:

Cpd # R¹ R² R¹ + R² R³ R⁴ R⁶ 1 H H I 4-(2-pyridin-4-ylami- Hno-thiazol-4-yl)phenyl 2 H H I 4-morpholin-4-ylphenyl H 3 H H Imorpholin-4-yl H 4 cyclo- I 4-morpholin-4-ylphenyl H propyl 5 H H I4-morpholin-4-ylphenyl CH₃ 6 H H I 4-[2-(4-methylpipera- Hzin-1-yl)-thia- zol-4-yl]phenyl 7 H H CH₃ 4-morpholin-4-ylphenyl H 8 H HCH₂CH₃ 4-morpholin-4-ylphenyl H

Presently Preferred Embodiments

While the broadest definition of this Invention is set forth in theSummary of the Invention, certain aspects of the Invention arepreferred.

-   (A) One preferred group of compounds is that wherein R¹ and R² are    hydrogen.-   (B) Another preferred group of compounds is that wherein R¹ and R²    form cycloalkyl, preferably cyclopropyl.-   (C) Another preferred group of compounds is that wherein R¹ and R²    form heterocycloalkyl, preferably piperidin-4-yl,    1-alkylpiperidin-4-yl (preferably, 1-methylpiperidin-4-yl),    morpholin-4-yl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl,    oxetanyl, azocanyl, oxocanyl, 1,3-, 1,4-, or 1,5-diazocanyl, 1,3-,    1,4-, or 1,5-dioxocanyl, 1,3-, 1,4-, or 1,5-oxazocanyl, 1,3-, 1,4-,    or 1,5-diazepanyl, 1,3-, 1,4-, or 1,5-dioxepanyl, 1,3-, 1,4-, or    1,5-oxazepanyl, tetrahydrothiophenyl, hexahydropyrimidinyl,    hexahydropyridazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,    dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl,    oxazolidinyl, thiomorpholinyl, thiothiomorphlinyl 1,1-dioxide,    imidazolidinyl, dioxanyl, or tetrahydropyridinyl.-   (D) Another preferred group of compounds is that wherein R¹ is    hydrogen and R² is haloalkyl.-   (E) Another preferred group of compounds is that wherein R¹ is    hydrogen and R² is hydroxyalkyl.

Within the above groups (A)-(E), a more preferred group of compounds isthat wherein:

-   -   R⁵ is hydrogen or methyl, preferably hydrogen; and    -   R⁶ is hydrogen or methyl, preferably hydrogen.

Within the above more preferred group, an even more preferred group ofcompounds is that wherein:

-   -   R³ is alkyl, preferably methyl, ethyl, or propyl.

Within the above more preferred group, another even more preferred groupof compounds is that wherein:

-   -   R³ is iodo.

Within the above preferred, more preferred, and even more preferredgroups, particularly preferred group of compounds are those wherein:

-   -   R⁴ is aryl, heteroaryl, or heterocyloalkyl optionally        substituted with one, two or three R^(a) wherein:    -   each R^(a) is independently selected from the group consisting        of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be        oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy,        nitro, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,        alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl,        heterocycloalkyl, arylamino, heteroarylamino,        heterocycloalkylamino, aryloxy, heteroaryloxy,        heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized        to sulfoxide or sulfone, heteroarylthio wherein the sulfur may        be oxidized to sulfoxide or sulfone, heterocycloalkylthio        wherein the sulfur may be oxidized to sulfoxide or sulfone,        cyano, acyl, carboxy, or alkoxycarbonyl wherein R^(a) is        optionally substituted with one, two or three R^(b) wherein:    -   each R^(b) is independently selected from the group consisting        of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be        oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy,        nitro, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,        alkylaminosulfonyl, dialkylaminosulfonyl, cyano, acyl, carboxy,        or alkoxycarbonyl.

Another particularly preferred group of compounds are those wherein:

-   -   R⁴ is selected from the group consisting of aryl, heteroaryl, or        heterocycloalkyl wherein R⁴ is optionally substituted with one,        two or three R^(a) wherein:        -   each R^(a) is independently selected from the group            consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, halo,            haloalkyl, haloalkoxy, nitro, amino, alkylamino,            dialkylamino, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,            dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl,            arylamino, heteroarylamino, heterocycloalkylamino, aryloxy,            heteroaryloxy, heterocycloalkyloxy, arylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone,            heteroarylthio wherein the sulfur may be oxidized to            sulfoxide or sulfone, heterocycloalkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,            carboxy, or alkoxycarbonyl provided that R⁴ is substituted            with at least one R^(a) that is an aryl, heteroaryl or            heterocycloalkyl ring or a group that has an aryl,            heteroaryl or heterocyclic ring and further wherein R^(a) is            optionally substituted with one, two or three R^(b) wherein:        -   each R^(b) is independently selected from the group            consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, halo,            haloalkyl, haloalkoxy, nitro, amino, alkylamino,            dialkylamino, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,            dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl,            arylamino, heteroarylamino, heterocycloalkylamino, aryloxy,            heteroaryloxy, heterocycloalkyloxy, arylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone,            heteroarylthio wherein the sulfur may be oxidized to            sulfoxide or sulfone, heterocycloalkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,            carboxy, or alkoxycarbonyl provided that R^(a) is            substituted with at least one R^(b) that is an aryl,            heteroaryl or heterocycloalkyl ring or a group that has an            aryl, heteroaryl or heterocyclic ring wherein each R^(b) is            optionally substituted with one, two or three substituents            independently selected from alkyl, alkoxy, hydroxy,            alkylthio wherein the sulfur may be oxidized to sulfoxide or            sulfone, halo, haloalkyl, haloalkoxy, carboxy,            alkoxycarbonyl, amino, alkylamino, dialkylamino,            aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,            aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,            cyano, or nitro.            (F) Another preferred group of compounds is that wherein R¹            and R² are hydrogen; and    -   R⁴ is selected from the group consisting of aryl, heteroaryl, or        heterocycloalkyl wherein R⁴ is optionally substituted with one,        two or three R^(a) wherein:        -   each R^(a) is independently selected from the group            consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, halo,            haloalkyl, haloalkoxy, nitro, amino, alkylamino,            dialkylamino, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,            dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl,            arylamino, heteroarylamino, heterocycloalkylamino, aryloxy,            heteroaryloxy, heterocycloalkyloxy, arylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone,            heteroarylthio wherein the sulfur may be oxidized to            sulfoxide or sulfone, heterocycloalkylthio wherein the            sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,            carboxy, or alkoxycarbonyl provided that R⁴ is substituted            with at least one R^(a) that is an aryl, heteroaryl or            heterocycloalkyl ring or a group that has an aryl,            heteroaryl or heterocyclic ring and further wherein R^(a) is            optionally substituted with one, two or three R^(b) wherein:    -   each R^(b) is independently selected from the group consisting        of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be        oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy,        nitro, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,        alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl,        heterocycloalkyl, arylamino, heteroarylamino,        heterocycloalkylamino, aryloxy, heteroaryloxy,        heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized        to sulfoxide or sulfone, heteroarylthio wherein the sulfur may        be oxidized to sulfoxide or sulfone, heterocycloalkylthio        wherein the sulfur may be oxidized to sulfoxide or sulfone,        cyano, acyl, carboxy, or alkoxycarbonyl provided that R^(a) is        substituted with at least one R^(b) that is an aryl, heteroaryl        or heterocycloalkyl ring or a group that has an aryl, heteroaryl        or heterocyclic ring wherein each R^(b) is optionally        substituted with one, two or three substituents independently        selected from alkyl, alkoxy, hydroxy, alkylthio wherein the        sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl,        haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino,        dialkylamino, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,        dialkylaminosulfonyl, cyano, or nitro.

Within this group, a more preferred group of compounds is that whereinR⁵ and R⁶ are hydrogen and R³ is iodo.

General Synthetic Scheme

Compounds of this invention can be made by the methods discussed below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

Compounds of Formula I can be prepared by methods described andillustrated in Schemes 1 and 2 below.

A compound of Formula I where R¹, R², R³, R⁴, R⁵ and R⁶ are as describedin the Summary of the Invention can be prepared as shown in Scheme 1below.

Reaction of an acid of formula 1 with a 3,5-diiodotyrosine derivative offormula 2 where X is hydrogen or alkyl (preferably methyl, ethyl, ortert-butyl) provides a compound of formula 3 or 5. The reaction iscarried out in the presence of a coupling agent such as HATU, EDC/HOBt,and the like to provide a compound of formula 3. Suitable organicsolvents for the above reactions are polar organic solvents such astetrahydrofuran, dioxane, dimethylformamide, and the like.

Alternatively, a compound of formula 2 where X is alkyl can be reactedwith an acid derivative e.g., an acid halide, of a compound of formula 1in the presence of a base such as triethylamine, pyridine, and the liketo provide a compound of formula 3.

Compounds of formula 1 such as benzoic acid, napthoic acid, nicotinicacid, 4-morpholin-4-ylbenzoic acid and isoincotinic acid arecommercially available. Other compounds of formula 1 can be prepared bymethods disclosed in PCT patent applications publication No. WO00/55126, U.S. Pat. No. 6,353,601, and Applicants PCT patent applicationNo. US 02/06533, the disclosures of which are incorporated herein byreference in their entirety. Compounds of formula 2 such as3,5-diiodotyrosine are commercially available. Others can be prepared bymethods well known in the art. For example, 3,5-diiodotyrosine can beconverted to its corresponding alkyl ester (X=alkyl) by it in thedesired alcohol such as methanol, ethanol, and the like in the presenceof an acid such as hydrochloric acid.

A compound of formula 3 can optionally be converted to a compound offormula 4 where R³ is alkyl by reacting 3 with alkyltin chloride. Thereaction is carried out in aqueous base such as aqueous potassiumhydroxide, and the like and in the presence of a palladium catalyst suchas palladium II chloride to give a mixture of dialkylated and themonoalkylated products. The desired monoalkylated product is isolated bycolumn chromatography. Alternatively, a compound of formula 4 where R³is ethyl can be prepared by the procedure described in working examplebelow.

Hydrolysis of the ester group in 3 under acidic (X=tert-butyl) or basic(X=methyl or ethyl) hydrolysis reaction conditions provides a compoundof formula 5. Reaction of 4 or 5 with an aminoacetonitrile compound offormula 6 where R¹ and R² are as defined in the Summary of the Inventionthen provides a compound of Formula I. The reaction is typically carriedout in the presence of a coupling agent such as HATU or HBTU. Compoundsof formula 6 such as 2-aminoacetonitrile are commercially available orthey can be prepared by methods well known in the art. Some such methodsare described in WO 00/55126 and Applicants PCT patent application No.US 02/06533 the disclosures of which are incorporated herein byreference in its entirety.

Alternatively, a compound of Formula I where R¹, R², R³, R⁴, R⁵ and R⁶are as described in the Summary of the Invention can be prepared asshown in Scheme 2 below.

Reaction of a compound of formula 7 with an aminoacetonitrile of formula6 under the reaction conditions described in Scheme 1 above, provides acompound of formula 8. Compound 7 can be readily prepared by reactingthe corresponding amino acid with BOC anhydride in the presence of abase such as sodium hydroxide, and the like.

Removal of the BOC group is carried out under acidic hydrolysis reactionconditions utilizing acids such as methanesulfonic acid, and the likeand in a suitable organic solvent such as tetrahydrofuran, and the like.

Compound 9 is then coupled with a compound of formula 1 under thereaction conditions described above to provide a compound of Formula I.

Detailed descriptions of synthesis of a compound of Formula I by theabove procedures are provided in working examples below.

Additional Processes for Preparing Compounds of Formula I:

Compounds of Formula I can also be prepared by modification of a grouppresent on a corresponding compound of Formula I. For example, acompound of Formula I where R⁶ is substituted with hydrogen can bealkylated with a suitable alkylating agent such astrialkyllsilyldiazomethane to provide a compound of Formula I where R⁶is alkyl.

A compound of Formula I can be prepared as a pharmaceutically acceptableacid addition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid. Alternatively, apharmaceutically acceptable base addition salt of a compound of FormulaI can be prepared by reacting the free acid form of the compound with apharmaceutically acceptable inorganic or organic base. Inorganic andorganic acids and bases suitable for the preparation of thepharmaceutically acceptable salts of compounds of Formula I are setforth in the definitions section of this application. Alternatively, thesalt forms of the compounds of Formula I can be prepared using salts ofthe starting materials or intermediates.

The free acid or free base forms of the compounds of Formula I can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of Formula I in an acid addition salt formcan be converted to the corresponding free base by treating with asuitable base (e.g., ammonium hydroxide solution, sodium hydroxide,etc.). A compound of Formula I in a base addition salt form can beconverted to the corresponding free acid by treating with a suitableacid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula I can be prepared by methods knownto those of ordinary skill in the art. For example, N-oxides can beprepared by treating an unoxidized form of the compound of Formula Iwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) ina suitable inert organic solvent (e.g., a halogenated hydrocarbon suchas methylene chloride) at approximately 0 C. Alternatively, the N-oxidesof the compounds of Formula I can be prepared from the N-oxide of anappropriate starting material.

Compounds of Formula I in unoxidized form can be prepared from N-oxidesof compounds of Formula I by treating with a reducing agent (e.g.,sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodiumborohydride, phosphorus trichloride, tribromide, etc.) in a suitableinert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane,etc.) at 0 to 80 C.

Prodrugs of the compounds of Formula I can be prepared by methods knownto those of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters.4:1985). For example, appropriate prodrugs can be prepared by reacting anon-derivatized compound of Formula I with a suitable carbamylatingagent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenylcarbonate, etc.).

Protected derivatives of the compounds of Formula I can be made by meansknown to those of ordinary skill in the art. A detailed description ofthe techniques applicable to the creation of protective groups and theirremoval can be found in T. W. Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, Inc. 1981.

Compounds of Formula I can be prepared as their individual stereoisomersby reacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds,separating the diastereomers and recovering the optically pureenantiomer. While resolution of enantiomers can be carried out usingcovalent diasteromeric derivatives of compounds of Formula I,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).

Pharmacology and Utility

The compounds of this invention are Cathepsin B inhibitors, and areuseful for treating diseases in which Cathepsin B activity contributesto the pathology and/or symptomatology e.g., cancer (see Michaud, S.;Gour, B. Exp. Opin. Ther. Pat. 1998, 8, 645, Koblinski, J. E. et al.Clinica Chim. Acta 2000, 291, 113, Berquin, I. M. and Sloane, BF Adv.Exp. Med. Biol. 1996, 389, 281, and Szpaderska, A. M. and Frankfater, A.Cancer Res. 2001, 61, 3493); neurodegenerative disorders (seePetanceska, S. et al. Neuroscience 1994, 59, 729); stroke (see Seyfried,D. M. et al. Brain Res. 2001, 901, 94); ischemia, rheumatoid arthritis(see Keyszer, G. et al. Arthritis Rheum. 1993, 41, 1378, Esser, R. E. etal. Arthritis Rheum. 1994, 37, 236, and Hashimoto, Y. et al. BiochemBiophys. Res. Commun. 2001, 283, 334); osteoarthritis (see Lang, A. etal. J. Rheumatol. 2000, 27, 1971); acute pancreatitis (see Halangk, W etal. J. Clin. Invest. 2000, 106, 773); liver disease (see Roberts, L. R.et al. Gastroenterology 1997, 113, 1714, Jones, B. A. et al. Am. J.Physiol. 1997, 272, G1109, Faubion, W. A. et al. J. Clin. Invest. 1999,103, 137, Roberts, L. R. et al. Cell Biochem. Biophys. 1999, 30, 71,Guicciardi, M. E. et al. J. Clin. Invest. 2000, 106, 1127, Guicciardi,M. E. et al. Hepatology 2001, 34, 844, and Guicciardi, M. E. et al. Am.J. Physiol 2001, 159, 2045); atherosclerosis (see Chen, J et alCirculation 2002, 105, 2766 and Li, W. et al Arterioscler. Thromb. Vasc.Biol. 2001, 21, 1124); Alzheimer's disease (see Tagawa, K. T. et alBiochem. Biophys. Res. Commun. 1991, 177, 377 and Cataldo, A. M. et al.Brain Res. 1990, 513, 181); and periodontal disease (see Eley, B. M. andCox, S. W. J. Periodontal Res. 1996, 31, 381).

Testing

The Cathepsin B inhibitory activities of the compounds of the inventioncan be determined by methods known to those of ordinary skill in theart. Suitable in vitro assays for measuring protease activity and theinhibition thereof by test compounds are known. Typically, the assaymeasures protease induced hydrolysis of a peptide based substrate.Details of assays for measuring protease inhibitory activity are setforth in Biological Examples 1 below.

Administration and Pharmaceutical Compositions

In general, compounds of Formula I will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with anothertherapeutic agent. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Forexample, therapeutically effective amounts of a compound of Formula Ifor anticoagulant therapy may range from 0.1 micrograms per kilogrambody weight (μg/kg) per day to 10 milligram per kilogram body weight(mg/kg) per day, typically 1 μg/kg/day to 0.1 mg/kg/day. Therefore, atherapeutically effective amount for a 80 kg human patient may rangefrom 10 μg/day to 10 mg/day, typically 0.1 mg/day to 10 mg/day. Ingeneral, one of ordinary skill in the art, acting in reliance uponpersonal knowledge and the disclosure of this Application, will be ableto ascertain a therapeutically effective amount of a compound of FormulaI for treating a given disease.

The compounds of Formula I can be administered as pharmaceuticalcompositions by one of the following routes: oral, systemic (e.g.,transdermal, intranasal or by suppository) or parenteral (e.g.,intramuscular, intravenous or subcutaneous). Compositions can take theform of tablets, pills, capsules, semisolids, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate composition and are comprised of, in general, a compound ofFormula I in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the activeingredient. Such excipient may be any solid, liquid, semisolid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, and the like. Liquid and semisolid excipientsmay be selected from water, ethanol, glycerol, propylene glycol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc.). Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose and glycols.

The amount of a compound of Formula I in the composition may vary widelydepending upon the type of formulation, size of a unit dosage, kind ofexcipients and other factors known to those of skill in the art ofpharmaceutical sciences. In general, a composition of a compound ofFormula I for treating a given disease will comprise from 0.01% w to 10%w, preferably 0.3% w to 1% w, of active ingredient with the remainderbeing the excipient or excipients. Preferably the pharmaceuticalcomposition is administered in a single unit dosage form for continuoustreatment or in a single unit dosage form ad libitum when relief ofsymptoms is specifically required. Representative pharmaceuticalformulations containing a compound of Formula I are described inFormulation Examples 1-3 below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1 Synthesis of(S)-N-[1-(cyanomethylcarbamoyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4-morpholin-4-yl-benzamide(compound 2)

Step 1

4-Morpholinobenzoic acid hydrochloride (0.488 g, 2.0 mmol), HOBT (0.297g, 2.2 mmol), and triethylamine (0.84 mL, 6.0 mmol) were stirred at roomtemperature with dry N,N-dimethylformamide (DMF) (20 mL). EDC (0.460 g,2.4 mmol) was added. After 30 min., a solution of L-3,5-diiodotyrosine(0.902 g, 2.0 mmol) in DMF (10.0 mL), triethylamine (0.84 mL, 6.0 mmol),and water (1.5 mL) was added. Stirring was continued for 16 hours. Thesolvent was then evaporated off and the residue was partitioned betweendichloromethane and 1N HCl. The organic phase was separated and driedover anhydrous magnesium sulfate. Filtration and solvent evaporationgave 816 mg of the crude(S)-3-(4-hydroxy-3,5-diiodo-phenyl)-2-(4-morpholin-4-yl-benzoylamino)-propionicacid that was used without purification for the following reaction.

Step 2

(S)-3-(4-Hydroxy-3,5-diiodo-phenyl)-2-(4-morpholin-4-yl-benzoylamino)-propionicacid (0.79 g), aminoacetonitrile hydrochloride (0.129 g, 1.27 mmol),HBTU (0.482 g, 1.27 mmol) and N-methylmorpholine (0.70 mL, 6.35 mmol)were dissolved in DMF (20 mL) and stirred overnight. The solvent wasevaporated and the residue was partitioned between 0.5 N HCl anddichloromethane in a separatory funnel. The organic phase was separated,washed with water, saturated sodium bicarbonate, and brine, and thendried over magnesium sulfate. Filtration and solvent evaporation gave480 mg of residue that was flash chromatographed on silica gel, elutingwith Mar. 7, 1990 (v/v/v) methanol/acetone/dichloromethane gave thetitle compound (115 mg) as a pink powder. Proton NMR (270 MHz, CDCl₃): δ9.33 (bs, 1H), δ 8.77 (t, J=6 Hz, 1H), δ 8.40 (d, J=8 Hz, 1H), δ 7.74(m, 4H), δ 6.95 (d, J=9 Hz, 2H), δ 4.55 (m, 1H), δ 4.18 (d, J=6 Hz, 2H),δ 3.73 (t, J=4 Hz, 4H), δ 3.21 (t, J=4 Hz, 4H), δ 2.68-2.97 (m, 2H).LCMS (electrospray) mH⁺ 661 (100%).

Proceeding as described in Example 1 above, but substituting appropriatestarting materials provided the following compounds of Formula I.

(S)-N-[1-(Cyanomethylcarbamoyl)-2-(4-hydroxy-3,5-diiodophenyl)-ethyl]4-[2-(pyridin-4-ylamino)-thiazol-4-yl]-benzamidetrifluoroacetate (compound 1). Proton NMR (270 MHz, DMSO-d6): δ 12.05(s, 1H), δ 9.36 (bs, 1H), δ 8.88 (t, J=5 Hz, 1H), δ 8.63 (d, J=6 Hz,2H), δ 8.09 (d, J=7 Hz, 4H), δ 7.94 (m, 3H), δ 7.77 (s, 2H), δ 4.62 (m,1H), δ 4.21 (d, J=5 Hz, 2H), δ 2.8-3.05 (m, 2H). LCMS (electrospray):mH⁺ 751 (100%).

(S)-Morpholine-4-carboxylic acid[1-(cyanomethyl-carbamoyl)-2-(4-hydroxy-3,5-diiodo-phenyl)-ethyl]-amide(compound 3). Proton NMR (270 MHz, DMSO-d6): δ 9.39 (bs, 1H), δ 8.66 (t,J=5 Hz, 1H), δ 7.61 (s, 2H), δ 6.72 (d, J=9 Hz, 1H), δ 4.2 (m, 3H), δ3.51 (t, J=5 Hz, 4H), δ 3.26 (m, 4H), δ 2.6-2.9 (m, 2H). LCMS(electrospray): mH⁺ 585 (100%).

(S)-N-[1-(1-Cyano-cyclopropylcarbamoyl)-2-(4-hydroxy-3,5-diiodo-phenyl)-ethyl]4-morpholin-4-yl-benzamide(compound 4). Proton NMR (270 MHz, DMSO-d6): δ 9.35 (bs, 1H), δ 9.00 (s,1H), δ 8.34 (d, J=8 Hz, 1H), δ 7.78 (d, J=9 Hz, 2H), δ 7.68 (s, 2H), δ6.96 (d, J=9 Hz, 2H), δ 4.46 (m, 1H), δ 3.73 (bt, 4H), δ 3.22 (bt, 4H),δ 2.85 (m, 2H), δ 1.48 (bs, 2H), δ 1.06 (bs, 2H). LCMS (electrospray):mH⁺ 687 (100%).

Example 2 Synthesis of(S)-N-[1-(cyanomethylcarbamoyl)-2-(3,5-diiodo-4-methoxyphenyl)ethyl]4-morpholin-4-yl-benzamide(compound 5)

(S)-N-[1-(Cyanomethyl-carbamoyl)-2-(4-hydroxy-3,5-diiodophenyl)-ethyl]4-morpholin-4-yl-benzamide(0.050 g, 0.076 mmol) was stirred with methanol (10 mL) and acetonitrile(10 mL). Trimethylsilyldiazomethane in hexanes (0.76 mL, 2.0 M, 0.15mmol) was added with stirring. After 2 hours the solvent was evaporatedand the residue was chromatographed on silica gel. Elution with 3/7/90methanol/acetone/dichloromethane provided the title compound (31.2 mg)as an off-white solid (a 61% yield).

Proton NMR (270 MHz, DMSO-d6): δ 8.77 (t, J=5 Hz, 1H), δ 8.44 (d, J=8Hz, 1H), δ 7.83 (s, 2H), δ 7.72 (d, J=9 Hz, 2H), δ 6.95 (d, J=9 Hz, 2H),δ 4.58 (m, 1H), δ 4.17 (m, 2H), δ 3.73 (br, 4H), δ 3.68 (s, 3H), δ 3.20(bt, 4H), δ 2.8-3.0 (m, 2H). LCMS (electrospray): mH⁺ 675 (100%).

Example 3 Synthesis of(S)-N-[1-(cyanomethyl-carbamoyl)-2-(4-hydroxy-3,5-diiodo-phenyl)-ethyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide(compound 6)

Step 1

2-tert-Butoxycarbonylamino-3-(4-hydroxy-3,5-diiodophenyl)-propionic acid2,5-dioxo-pyrrolidin-1-yl ester (1.00 g, 1.59 mmol), available fromBachem, aminoacetonitrile (176 mg, 1.90 mmol), and N-methylmorpholine(0.42 mL, 3.8 mmol) were stirred at room temperature in 25 mL dryacetonitrile. After 16 h, the solvent was rotary evaporated and theresidue was partitioned between ethyl acetate and 0.5 N aqueous HCl in aseparatory funnel. The organic phase was washed with water, and brine,and dried over anhydrous magnesium sulfate. Filtration and solventevaporation afforded 450 mg of[1-(cyanomethylcarbamoyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-carbamicacid tert-butyl ester as a yellow solid (50%). This was used withoutpurification for the subsequent step.

Step 2

To a solution of(S)-[1-(cyanomethylcarbamoyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-carbamicacid tert-butyl ester (1.88 g, 3.30 mmol) in 100 mL anhydrous THF wasadded anhydrous methanesulfonic acid (1.20 mL, 16.5 mmol). After 17hours the volume of the reaction mixture was reduced by half. Theremaining solution was vigorously stirred while diethyl ether was added.The white precipitate was collected, rinsed with anhydrous ether, driedbriefly to give(S)-2-amino-N-cyanomethyl-3-(4-hydroxy-3,5-diiodo-phenyl)-propionamidemethanesulfonate (1.14 g), which was used immediately for the subsequentcoupling without further purification.

Step 3

To a mixture of 4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoicacid hydrobromide (prepared as described in PCT patent applicationspublication No. WO 00/55126) (0.680 g, 1.76 mmol),(S)-2-amino-N-cyanomethyl-3-(4-hydroxy-3,5-diiodo-phenyl)-propionamidemethanesulfonate (1.00 g, 1.76 mmol), and HATU (0.671 g, 1.76 mmol) wasadded triethylamine (1.47 mL, 10.6 mmol). The reaction mixture wasstirred for 2 hours and then the solvent was removed by evaporation. Theresidue was taken up in a minimum amount of 15% (v/v) methanol indichloromethane and stirred while diethyl ether was added. Theprecipitate was collected by filtration, washed with more ether, anddried. Flash chromatography of this material was carried out on silicagel, applying the sample with 50% methanol in dichloromethane andeluting the column with 10% methanol in dichloromethane to give thetitle compound (426 mg) as a pink solid (a 32% yield). Proton NMR (270MHz, CDCl₃): δ 8.83 (t, J=6 Hz, 1H), δ 8.69 (d, J=8 Hz, 1H), δ 7.94 (d,J=8 Hz, 2H), δ 7.82 (d, J=8 Hz, 2H), δ 7.75 (s, 2H), δ 7.45 (s, 1H), δ4.61 (m, 1H), δ 4.18 (d, J=6 Hz, 2H), δ 3.47 (bt, 4H), δ 2.75-3.05 (m,2H), δ 2.45 (bt, 4H), δ 2.24 (s, 3H). LCMS (electrospray) mH⁺ 757(100%).

Example 4 Synthesis of(S)-N-[1-(cyanomethyl-carbamoyl)-2-(3-ethyl-4-hydroxy-5-iodo-phenyl)-ethyl]4-morpholin-4-yl-benzamide(compound 8)

Step 1

In a 500 mL roundbottom flask was placed p-morpholinobenzoic acidhydrochloride (2.0 g, 8.2 mmol), diiodotyrosine ethyl ester bisulfate(3.78 g, 8.2 mmol) and HATU (3.15 g, 8.29 mmol). The solids were takenup with vigorous stirring in DMF (50 mL) and triethylamine (6 mL). Thereaction was allowed to proceed overnight. The reaction solution wasconcentrated in vacuo to give a red oil, which was eluted through a plugof silica gel using ethyl acetate. The eluted material was concentratedin vacuo to give a yellow solid. This was dissolved in a minimum amountof boiling methanol. The methanolic solution was allowed to cool to roomtemperature and then made to stir vigorously while the slow addition ofwater led to the precipitation of yellow solids. The mixture wasrefrigerated overnight. The precipitate was filtered and dried to give3-(3,5-diiodo-4-hydroxy-phenyl)-2-(4-morphilin-4-yl-benzoylamino)-propionicacid ethyl ester (3.31 g) as a yellow solid.

Step 2

In a 100 mL roundbottom flask equipped with stir bar was placedmethyltin trichloride (1.00 g, 4.17 mmol). The solid was taken up in 10%aqueous KOH that was sparged with nitrogen and stirred. To this solutionwas added a catalytic amount (5 mg) of palladium(II) chloride followedby the rapid addition of3-(3,5-diiodo-4-hydroxy-phenyl)-2-(4-morpholin-4-yl-benzoylamino)-propionicacid ethyl ester (1.11 g, 1.71 mmol). The reaction was heated to 90° C.and stirred for 14 hours. The solution was acidified with 1.0 N HCl andextracted with ethyl acetate. The organic fraction was dried over MgSO₄.Filtration and solvent evaporation gave a crude product, which wasdissolved in DMF and 1.0 mL triethylamine followed by addition of HATU(0.195 g, 0.512 mmol) and aminoacetonitrile hydrochloride (0.070 g,0.757 mmol). After 4 hours, the reaction mixture was poured into ethylacetate and washed with 10% citric acid, saturated sodium bicarbonateand brine. The organic fraction was dried over MgSO₄. Filtration andsolvent evaporation followed by reversed-phase HPLC purification of theresidue gave the(S)-N-[1-(cyanomethyl-carbamoyl)-2-(3,5-diethyl-4-hydroxy-5-iodo-phenyl)-ethyl]-4-morpholin-4-yl-benzamideas the trifluoroacetate salt (0.049 g) as a white solid (a 7% overallyield). Proton NMR (300 MHz, DMSO-d6) δ 8.7 (t, 1H) d 8.3 (t, 1H) δ 7.7(d, 2H) δ 6.9 (m, 4H) δ 6.9 (d, 2H) δ 4.5 (m, 1H) δ 4.1 (d, 2H) δ 3.7(m, 4H) δ 3.6 (s, 3H) δ 3.2 (m, 4H) δ 3.0-2.8 (m, 2H) δ 2.1 (s, 6H). MS(electrospray): mH⁺ 450.5 (100%) andN-[1-(cyanomethyl-carbamoyl)-2-(4-hydroxy-3-iodo-5-methylphenyl)-ethyl]-4-morpholin-4-yl-benzamide.Proton NMR (300 MHz, DMSO-d6) δ 8.6 (t, 1H) δ 8.3 (t, 1H) δ 7.7 (d, 2H)δ 7.5 (s, 1H) δ 7.0 (s, 1H) δ 6.9 (d, 2H) δ 4.5 (m, 1H) δ 4.1 (m, 2H) δ3.7 (m, 4H) δ 3.2 (m, 4H) δ 3.0-2.8 (m, 2H) δ 2.1 (s, 3H). MS(electrospray): mH⁺ 549.2 (100%).

Example 5 Synthesis of(S)-N-[1-(cyanomethyl-carbamoyl)-2-(3-ethyl-4-hydroxy-5-iodo-phenyl)-ethyl]4-morpholin-4-yl-benzamide(compound 8)

Step 1

In a sealed tube equipped with a stir bar were placed3-(4-hydroxy-3-iodophenyl)-2-(4-morpholin-4-yl-benzoylamino)-propionicacid ethyl ester (1.15 g, 2.14 mmol). The solid was taken up in1,4-dioxane (5 mL) and triethylamine (1 mL). To the stirring solutionwas added dichlorobis-(triphenylphosphine)palladium (II) (15 mg) andcopper(I) iodide (7 mg) followed by (trimethylsilyl)acetylene (0.34 mL).The reaction mixture was sealed and placed in a 60° C. oil bath andallowed to proceed overnight. The mixture was diluted with ethyl acetateand filtered through celite filter aid. The organic solution was washedwith 1.0 N HCl, sodium bicarbonate and brine. The solution was driedover MgSO₄. Filtration and solvent evaporation gave a thick oily residuethat was used in the next step without purification.

Step 2

The crude product from Step 1 above, was taken up in tetrabutylammoniumfluoride (10 mL of a 1.0 M solution in THF). After one hour, thesolution was again concentrated in vacuo. This residues were then takenup in ethanol with 10% palladium on carbon (25 mg) and hydrogenated in aParr shaker overnight. After filtering through celite and concentratingin vacuo, the residue was chromatographed on silica gel using 1:1hexane:ethyl acetate as the eluent. The crude product was then taken upin 15 mL dichloromethane and cooled to 0° C. in an ice bath. To thissolution were added aluminum trichloride (0.9 g, 6.75 mmol) andethanethiol (0.950 mL, 12.8 mmol). The mixture was allowed to warm to RTwhile stirring for 2 hours. LCMS indicated complete demethylation of thephenol. Volatiles were removed in vacuo. Residues were dissolved indichloromethane and washed with 1.0 N HCl, saturated sodium bicarbonateand brine. The organic fraction was dried over MgSO₄ and filtered.Volatiles were removed in vacuo. Potassium iodide (0.115 g, 0.697 mmol)was added to the solid residues and the two were taken up in ammoniumhydroxide with stirring followed by the addition of iodine crystals(0.177 g, 0.697 mmol). The solution quickly decolorized and was allowedto stir for one hour. The reaction was neutralized with the addition ofacetic acid. The mixture was then transferred to a separatory funnel andextracted with dichloromethane. LCMS of the organic extract showed onlythe desired product.

The residues obtained from removal of solvent were taken up in 10 mL oftetrahydrofuran and 10 mL of water, followed by the addition of lithiumhydroxide (0.350 g, 8.34 mmol). After stirring for one hour, thereaction mixture was acidified with the addition of acetic acid. Thereaction mixture was again extracted with dichloromethane. The organiclayer was dried in vacuo. The solids obtained were taken up in DMF andtriethylamine with stirring, followed by the addition of HATU (0.203 g,0.509 mmol) and aminoacetonitrile hydrochloride (0.060 g, 0.650 mmol)and allowed to stir overnight. Solvents were removed in vacuo and theresidues were purified by reversed phase HPLC to give 10 mg of the titlecompound as a waxy white solid (a 2.5% overall yield). Proton NMR (300MHz, DMSO-d6): δ 8.8 (t, 1H) δ 8.4 (d, 1H) δ 7.7 (d, 2H) δ 7.5 (s, 1H) δ7.05 (s, 1H) δ 6.95 (d, 2H) δ 4.5 (m, 1H) δ 4.1 (m, 2H) δ 3.7 (m, 4H) δ3.2 (m, 4H) δ 3.0-2.8 (m, 2H) δ 2.5 (q, 2H) δ 2.1 (t, 3H). MS(electrospray): mH⁺ 562.4 (100%).

FORMULATION EXAMPLES

Representative Pharmaceutical Formulations Containing a Compound ofFormula I are as described below:

Example 1 Oral Formulation

Compound of Formula I 10-100 mg Citric Acid Monohydrate 105 mg SodiumHydroxide 18 mg Flavoring water qs to 100 ml

Example 2 Intravenous Formulation

Compound of Formula I 0.1 to 10 mg Dextrose Monohydrate q.s. to makeisotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Waterfor Injection q.s. to 1.0 mL

Example 3 Tablet Formulation

Compound of Formula I  1% Microcrystalline Cellulose 73% Stearic Acid25% Colloidal Silica  1%

BIOLOGICAL EXAMPLES Example 1 Cathepsin B Assay

Solutions of test compounds (varying concentrations in 10 μL of DMSO)were diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 6);polyoxyethylenesorbitan monolaurate, 0.001%; EDTA (2.5 mM); and DTT, 2.5mM). Human Cathepsin B (0.1 pMoles in 25 μL of assay buffer) was addedto the dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 minutes at room temperature.BOC-LKR-AMC (8 nMoles in 25 μL of assay buffer) was added to the assaysolutions and hydrolysis was followed by fluorescence spectroscopy (ex355 nm, em 460 nm) for 5 minutes. Apparent inhibition constants (K_(i))were calculated from the enzyme progress curves using standardmathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit Cathepsin B inhibitory activity.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled. All patents, patent applications andpublications cited in this application are hereby incorporated byreference in their entirety for all purposes to the same extent as ifeach individual patent, patent application or publication were soindividually denoted.

1. A compound of Formula I:

wherein: R¹ and R² are independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, aryl, or aralkyl; or R¹ and R² together with the carbonatom to which they are attached form cycloalkyl or heterocycloalkyl; R³is alkyl or iodo; and R⁴ is selected from the group consisting of aryl,heteroaryl, or heterocycloalkyl wherein R⁴ is optionally substitutedwith one, two or three R^(a) wherein: each R^(a) is independentlyselected from the group consisting of alkyl, alkoxy, hydroxy, alkylthiowherein the sulfur may be oxidized to sulfoxide or sulfone, halo,haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl,heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino,aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfurmay be oxidized to sulfoxide or sulfone, heteroarylthio wherein thesulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthiowherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,carboxy, or alkoxycarbonyl wherein R^(a) is optionally substituted withone, two or three R^(b) wherein: each R^(b) is independently selectedfrom the group consisting of alkyl, alkoxy, hydroxy, alkylthio whereinthe sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl,haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl,heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino,aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfurmay be oxidized to sulfoxide or sulfone, heteroarylthio wherein thesulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthiowherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl,carboxy, or alkoxycarbonyl wherein each R^(b) is optionally substitutedwith one, two or three substituents independently selected from alkyl,alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, cyano, or nitro; R⁵ and R⁶ areindependently hydrogen or alkyl; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein R¹ and R² are hydrogen. 3.The compound of claim 1 wherein R¹ and R² form cycloalkyl.
 4. Thecompound of claim 1 wherein R¹ and R² form heterocycloalkyl.
 5. Thecompound of claim 1 wherein wherein R¹ is hydrogen and R² is haloalkyl.6. The compound of any of the claims 2-6 wherein: R⁵ is hydrogen ormethyl; and R⁶ is hydrogen or methyl.
 7. The compound of claim 6 whereinR³ is alkyl.
 8. The compound of claim 6 wherein R³ is iodo.
 9. Thecompound of claim 7 wherein: R⁴ is aryl, heteroaryl, or heterocyloalkyloptionally substituted with one, two or three R^(a) wherein: each R^(a)is independently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl whereinR^(a) is optionally substituted with one, two or three R^(b) wherein:each R^(b) is independently selected from the group consisting of alkyl,alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, cyano, acyl, carboxy, or alkoxycarbonyl.
 10. Thecompound of claim 8 wherein: R⁴ is aryl, heteroaryl, or heterocyloalkyloptionally substituted with one, two or three R^(a) wherein: each R^(a)is independently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl whereinR^(a) is optionally substituted with one, two or three R^(b) wherein:each R^(b) is independently selected from the group consisting of alkyl,alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, cyano, acyl, carboxy, or alkoxycarbonyl.
 11. Thecompound of claim 7 wherein: R⁴ is selected from the group consisting ofaryl, heteroaryl, or heterocycloalkyl wherein R⁴ is optionallysubstituted with one, two or three R^(a) wherein: each R^(a) isindependently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl providedthat R⁴ is substituted with at least one R^(a) that is an aryl,heteroaryl or heterocycloalkyl ring or a group that has an aryl,heteroaryl or heterocyclic ring and further wherein R^(a) is optionallysubstituted with one, two or three R^(b) wherein: each R^(b) isindependently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl providedthat R^(a) is substituted with at least one R^(b) that is an aryl,heteroaryl or heterocycloalkyl ring or a group that has an aryl,heteroaryl or heterocyclic ring wherein each R^(b) is optionallysubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may beoxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, cyano, or nitro.
 12. Thecompound of claim 8 wherein: R⁴ is selected from the group consisting ofaryl, heteroaryl, or heterocycloalkyl wherein R⁴ is optionallysubstituted with one, two or three R^(a) wherein: each R^(a) isindependently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl providedthat R⁴ is substituted with at least one R^(a) that is an aryl,heteroaryl or heterocycloalkyl ring or a group that has an aryl,heteroaryl or heterocyclic ring and further wherein R^(a) is optionallysubstituted with one, two or three R^(b) wherein: each R^(b) isindependently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl providedthat R^(a) is substituted with at least one R^(b) that is an aryl,heteroaryl or heterocycloalkyl ring or a group that has an aryl,heteroaryl or heterocyclic ring wherein each R^(b) is optionallysubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may beoxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, cyano, or nitro.
 13. Thecompound of claim 1 wherein R¹ and R² are hydrogen; and R⁴ is selectedfrom the group consisting of aryl, heteroaryl, or heterocycloalkylwherein R⁴ is optionally substituted with one, two or three R^(a)wherein: each R^(a) is independently selected from the group consistingof alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidizedto sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino,heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy,heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidizedto sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may beoxidized to sulfoxide or sulfone, cyano, acyl, carboxy, oralkoxycarbonyl provided that R⁴ is substituted with at least one R^(a)that is an aryl, heteroaryl or heterocycloalkyl ring or a group that hasan aryl, heteroaryl or heterocyclic ring and further wherein R^(a) isoptionally substituted with one, two or three R^(b) wherein: each R^(b)is independently selected from the group consisting of alkyl, alkoxy,hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl,heteroaryl, heterocycloalkyl, arylamino, heteroarylamino,heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy,arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone,heteroarylthio wherein the sulfur may be oxidized to sulfoxide orsulfone, heterocycloalkylthio wherein the sulfur may be oxidized tosulfoxide or sulfone, cyano, acyl, carboxy, or alkoxycarbonyl providedthat R^(a) is substituted with at least one R^(b) that is an aryl,heteroaryl or heterocycloalkyl ring or a group that has an aryl,heteroaryl or heterocyclic ring wherein each R^(b) is optionallysubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may beoxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, cyano, or nitro.
 14. Apharmaceutical composition comprising a compound of any of the claim1-14 in admixture with one or more pharmaceutically suitable excipients.15. A method of treating a disease in an animal in which inhibition ofCathepsin B, can prevent, inhibit or ameliorate the pathology and/orsymptomatology of the disease, which method comprises administering tothe animal a pharmaceutical composition comprising a therapeuticallyeffective amount of compound of any of the claims 1-14 or apharmaceutically acceptable salt thereof.